1-phenylsulfonyl-2-(2-thiazolin-2-yl-oxy and thiol) pyrrolidines



United States Patent Int. Cl. C07d 91/24, 91/28 US. 'Cl. 260306.7 2 Claims ABSTRACT OF THE DISCLOSURE This invention relates generally to 2-substituted l-arylsulfonyl pyrrolidine compounds 'and to starting materials for preparing the former, and, more particularly, to novel p-substituted-phenylsulfonyl pyrrolidine derivatives having pharmacological activity, and to valuable intermediates for preparing said novel derivatives.

This is a division of an application Ser. No. 536,479, now US. Patent No. 3,453,289, July 1, 1969 filed Jan. 21, 1966.

The novel pharmacologically active p-su-bstituted-phenylsulfonyl pyrrolidine derivatives encompassed by the 3,501,489 Patented Mar. 17, 1970 wherein R and R are each selected from the group consisting of hydrogen, alkyl, halogen, nitro and acylamine; R and R are each selected from the group consisting of hydrogen, alkyl, halogen, nitro, amino and acylamino; R is selected from the group consisting of alkyl, halogen, nitro, amino and acylamino; Y is selected from the group consisting of oxygen and sulfur; and R is selected from the group consisting of alkyl, provided that R is other than methyl; dialkylaminoalkyl; alkoxyalkyl; alkylthicalkyl; phenyl; halophenyl; benzyl; haloalkylphenyl; thienyl; furyl; thiazolinyl; cycloalkyl; and a second p-substituted-phenylsulfonyl pyrrolidine group of the similar general formula:

present invention are those having the following general f formula: R SO2NH(CH2)3OH(0R7)z A 14 R2 R I I 3 wherein R R R R and R are as defined for the compounds of Formula A above; and R is alkyl.

| I I The general syntheses of the compounds of Formulae A and B above are represented schematically below wherein R R R R R R and R have the same meanings as in said formulae:

R2 R1 R2 R1 I I I I R 'SO2Cl+HzN(CH2)3CH(OR R,@-so2NH oH2),oH oR 2 (I) (II) (III) F R2 R1 H+ I R SO2NOR R2 Rl R1 52 HOCHzOHzOH n SO2N OCHzCHzO -NS02-@R R R! U U I R4 R5 5 R4 8 0 NH CH CH 0R (v) R S 2 2): )2 R2 R1 I I Ra Ra n (III) HSCH2CH2N(C2H5)2 ----r R3 S02N- l'SCHzCH2N(C2H )z R2 R1 HS -s I 11+ U R @SO -NSH-S I I N I R4 R5 k/( DV In preparing the compounds of the invention, a phenylsulfonyl chloride (I) in an inert solvent such as dimethoxyethane is added to a cold solution of an aminoacetal (II). The reaction solution is stirred, benzene is added and the mixture is then extracted with water. The organic layer is dried and the solvent is removed under reduced pressure to give the benzenesulfonamide denoted by Formula III. Treatment of this compound in alcohol with mineral acid causes ring closure to form the pyrrolidine (IV).

The bis compounds denoted by Formula V are prepared by dissolving the sulfonamide compounds of Formula III in ethylene glycol (or ethylene dithiol when the thio analogs are desired) containing a trace of a mineral acid such as hydrochloric acid and heating to around 50 to 80 C. The resulting product precipitates upon standing overnight and can be recrystallized from benzene.

Treatment of compounds of Formula III with a mercapto-tertiary amine in the presence of a mineral acid yields the 2-dialkylaminoalkylthio compounds of Formula VI. Similarly, treatment of said compounds of Formula III with a thiophenol yields the corresponding 2-phenylthiopyrrolidine compounds. In like manner, treatment of compounds of Formula III in acid medium with a mercapto-thiazine gives the corresponding 2-thiazinylthiopyrrolidine compounds (VII).

It has been discovered that compounds of Formula A. meeting the described qualifications, have useful pharmacological properites. More specifically, said compounds have been found to exhibit utility as central nervous system, diuretic and antiviral agents.

When the compounds of Formula A are employed for their central nervous system, diuretic and antiviral activity in mammals, they may be administered alone or in combination with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of admintration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets or capsules containing conventional excipients, or in the form of solutions; or they may be injected parenterally, that is intramuscularly, intravenously or subcutaneously. For parenteral administration they may be used in the form of sterile solutions containing other solutes, for example, enough saline or glucose to make the solutions isotonic.

The dosage of the present therapeutic agents will vary with the form of administration and the particular compound chosen. It will generally be found that when the composition is administered orally, larger quantities of the active agent will be required to produce the same effect as a smaller quantity given parenterally. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects and preferably at a level that is in the range of from about 0.1 mg. to about 7 mg. per kg. of body weight per day, although as aforementioned variations will occur. However, a dosage level that is in the range of from about 0.2 mg. to about 2 mg. per kg. of body Weight per day is most desirably employed in order to achieve effective results.

The following examples are given by way of illustration.

EXAMPLE I p-Nitro-N (4,4-diethoxybutyl) -benzenesulfonamide p-Nitrobenzenesulfonyl chloride (22.10 g. or 0.10 m.) was slowly added to a cold dimethoxyethane solution of 'y-aminobutyraldehyde diethyl acetal (19.30 g. 0.12 m.) containing 20 g. of triethylamine. After the solution was stirred for 20 minutes, benzene was added, followed by extraction of water. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed at re u ed press re. The residue was recrystallized from a mixture of benzene and cyclohexane, M.P. 5860 C.

Elemental analysis confirmed the empirical formula for CMHZZNZOGS.

EXAMPLE II 2-ethoxy-1-(p-nitrophenylsulfonyl)pyrrolidine p-Nitro-(4,4-diethoxybutyl) -benzenesulfonamide 10.0 g.), prepared in accordance with Example I, was dissolved in ethyl alcohol. The solution was heated on a steam bath, in the presence of a few drops of cone. hydrochloric acid, for 10 min. The solution was cooled and the solid was collected. The compound can be recrystallized from n-hexane, M.P. 702 C.

Elemental analysis confirmed the empirical formula for C H N O S.

EXAMPLE III p-B romo-N- 4,4-diethoxybutyl) -benzenesulfonamide p-Bromobenzenesulfonyl chloride 10.20 g. or 0.04 In.) was slowly added to a cold dimethoxyethane solution of y-aminobutyraldehyde diethyl acetal (8.0 g. or 0.05 m.), containing 10 g. of triethyl amine. After the solution was stirred for 20 min., benzene was added, followed by extraction of water. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed at reduced pressure. The residual solid was recrystallized from cyclohexane to give 13 g. of material, M.P. 878 C.

Elemental analysis confirmed the empirical formula for C I-I BrNO S.

. 7 EXAMPLE *IV 1- (p-Bromophenylsulfonyl) -2-ethoxypyrrolidine p-BromoN-(4,4 diethoxybutyl) benzenesulfonamide (10 g.) of Example III was dissolved in 30 ml. of ethyl alcohol and the solution heated on a steam bath for 30 min. in the presence of 8 drops of cone. hydrochloric acid. After the solvent was removedat reduced pressure, the residue was recrystallized from cyclohexane, M.P. 51-3 C.

Elemental analysis confirmed the empirical formula for C12H16BI'N03S.

EXAMPLE V 2,2'-ethylenedioxybis 1- (p bromophenylsulfonylpyrrolidine] p Bromo N (4,4 diethoxybutyl) benzenesulfonamide of Example 1H (12.0 g. or 0.0313 m.) was dissolved in 50 ml. of ethylene glycol and heated on a steam bath, in the presence of 5 drops of hydrochloric acid, for 1 hour. The solution was let stand at room temperature overnight. The solid was collected and washed with ethyl alcohol. 8.0 g. was obtained. The compound was recrystal lized from benzene, M.P. 188-190 C. I

Elemental analysis confirmed the empirical formula for CZZHZGBI'ZNZOGSZ.

EXAMPLE VI 1 p-aminophenylsulfonyl-Z-ethoxypyrrolidine The amino compound is prepared from the correspondmg l-p-nitro compound by catalytic hydrogenation using a platinum oxide catalyst.

'EMMPLE VII 1 (p-bromophenylsulfonyl) -2- [2- diethylamino) ethylthio] pyrrolidine hydro chloride p Bromo N (4,4 diethoxybutyl) benenesulfonamide of Example III (3.80 g. or 0.01 m.) and -N,N-diethylamino-ethanethiol hydrochloride (2.50 g. or 0.015 In'.) were dissolved in 50 ml. of isopropyl alcohol and the solution heated on a steam bath, in the presence of 1 drop of cone. hydrochloride, for 3 hours. The solution was con-. centrated at reduced pressure and the residue recrystallized from isopropyl alcohol, M.P- 127-8 C.

Elemental analysis confirmed the empirical formula for C16H25BIN2O2S2 'HCI.

EXAMPLE VIII 1-(p-bromophenylsulfonyl) -2-(2-thiazolin-2-yl-thio) pyrrolidine p Bromo N (4,4 diethoxybutyl) benzenesulfonamide of Example III (10.0 g. or 0.263 m.) and 2-mercaptothiazoline (5.0 g. or 0.0425 111.) were dissolved in dioxane and the solution heated on a steam bath for 30 minutes in the presence of a few drops of concentrated HCl. A small amount of insoluble material was filtered off and the filtrate concentrated. The residue was recrystallized from dioxane to give 5.10 g., M.P. 183-5 C.

Elemental analysis confirmed the emp rical formula for C13H15BI'N202S3.

EXAMPLE IX p-Acetamido-N- (4,4-diethoxybutyl) benzenesulfonamide p-Acetamidobenzenesulfonyl chloride (27.5 g. or 0.118 In.) was gradually added to a cold dimethoxyethane solution of 'y-aminobutyraldehyde diethyl acetal, containing 12.7 g. of triethylamine. The solution was stirred for 2 hours. Benzene was added and the solution extracted with water. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed at a reduced pressure. The residue was recrystallized from isopropanol to give 26.0 g., M.P. 102-4 C.

Elemental analysis confirmed the empirical formula for C16H26N2O5S.

EXAMPLE X 4'- (2-cth oxyl-pyrrolidinylsulfonyl) -acetanilide p-Acetamido N (4,4-diethoxybutyl)-benzenesulfonamide (8.00 g. or 0.0223 m.), prepared as in Example IX, was dissolved in C H OH and the solution was let stand at room temperature in the presence of 5 drops of cone. hydrochloric acid. The solid was collected and rinsed with ethyl alcohol. This gave 4.50 g. of a solid melting at 1l3-5 C.

Elemental analysis confirmed the empirical formula for C14H20N2O4S.

EXAMPLE XI 1- p-chloro-o-toluenesulfonyl) -2-ethoxypyrrolidine A dimethoxyethane solution of p-chloro-o-toluenesulfonyl chloride is slowly added to a cold solution of 'yaminobutyraldehyde dimethyl acetal and triethylamine in the same solvent. The mixture is stirred for 15 minutes and benzene is then added. The resulting benzene solution is first washed with water and then dried over anhydrous magnesium sulfate. After the drying agent is removed, benzene is removed at reduced pressure. The residue is then dissolved in ethanol. After a few drops of hydrochloric acid are added to the ethanol solution, the latter is left to stand at room temperature overnight. Ethanol is thereafter removed at reduced pressure, and the resulting residue is recrystallized from ethanol to give l-(p-chloro-o-toluenesulfonyl)-2-ethoxypyrrolidine.

EXAMPLE XII 1-p-ethylphenylsulfonyl-2-ethylthioethylthiopyrrolidine The above compound is prepared by reacting N-(4,4- diethoxybutyl) p ethylbenzenesulfonamide with 2-ethylthioethyl mercaptan according to the procedure of Example IV.

EXAMPLE XIII 1-p-bromophenylsulfonyl-2-phenylthiopyrrolidine The above compound is prepared by reacting p-bromo- N (4,4 diethoxybutyl) benzenesulmonamide with thiophenol according to the procedure of Example IV.

6 EXAMPLE XIV 1-p-tolysulfonyl-2-cyclohexyloxy-pyrrolidine The title compound is prepared by reacting N-(4,4-diethoxybutyl)-p-tolylsulfonamide with cyclohexanol according to the procedure of Example IV.

EXAMPLE XV 2,2'-ethylenedithiobis-(2,4-dimethylbenzenesulfonylpyrrolidine) The above compound is prepared by reacting N-(4,4- diethoxybutyl) 2,4 dimethylbenzenesulfonamide with ethylenedithiol according to the procedure of Example V.

EXAMPLE XVI m-Chloro-N- 4,4-diethoxybutyl) -p-toluenesulfonamide By following the procedure of Example I and using m-chloro-p-toluenesulfonyl chloride instead of p-nitrobenzenesulfonyl chloride as starting material, the above compound is prepared.

EXAMPLE XVII 1- (m-chloro-p-toluenesulfonyl -2-ethoxypyrrolidine By following the procedure of Example II, but substituting rn chloro N (4,4-diethoxybutyl) -p-toluenesulfonamide as starting material, the above compound is prepared.

- EXAMPLE XVIII m-Amino-pchloro-N-(4,4-diethoxybutyl)benzenesulfonamide Again following the procedure of Example I, but in this instance using m-amino p-chlorobenzesulfonyl chloride as starting material, the above compound is prepared.

EXAMPLE XIX 1(m-amino-p-chlorophenylsulfony1)-2-ethoxypyrrolidine Utilizing the procedure of Example II, and substituting m-amino-p-chloro N (4,4-diethoxybutyl)benzenesulfonamide as starting material, the above compound is prepared.

EXAMPLE XX m-Amino-p-chloro-N-(4,4-diethoxybutyl)-otoluenesulfonamide Using m-amino-p-chloro-o-toluenesulfotiyl chloride as starting material in the procedure of Example I, the above compound is obtained.

EXAMPLE XXI 1- (m-amino-p-chloro-o-toluenesulfonyl)-2- ethoxypyrrolidine wherein R and R are each selected from the group consisting of hydrogen, lower alkyl, halogen, nitro and lower alkanoylamino; R and R are each selected from the group consisting of hydrogen, lower alkyl, halogen, nitro, amino and lower alkanoylamino; R is selected from the 7 8 group consisting of alkyl, halogen, nitro, amino and lower References Cited alkamylammiand Z I UNITED STATES PATENTS -NY-R U r 3,453,289 7/1969 Wei et al. 260--326.82

5 HENRY R. J ILES, Primary Examiner wherein R is thiazolinyl; and Y is selected from the C, M, SHURKO, A i t t E i group consisting of oxygen and sulfur. I

2. A compound as defined in claim 1 which is: l-(pv I US. Cl. 'X.R. bromophenylsulfonyl) 2 (2 thiazolin 2 yl thio) 10 260238.95 pyrrolidine; I v 

